Dasatinib salts

Abstract

The invention relates to normal or acidic salts of dasatinib and the hydrate and solvate forms thereof. More specifically the invention concerns: dasatinib cyclamic acid salt, dasatinib cyclamic acid (1:1) salt Form I, dasatinib cyclamic acid (1:1) salt Form II, dasatinib hydrogen bromide (1:2) salt, dasatinib methane sulfonic acid (1:2) salt, dasatinib p-toluenesulfonic acid (1:1) dihydrate salt, anhydrous dasatinib p-toluenesulfonic acid (1:1) salt Form I, anhydrous dasatinib p-toluenesulfonic acid (1:1) salt Form II, dasatinib p-toluenesulfonic acid (1:1) salt methanol solvate. Moreover the invention relates process for preparing dasatinib salts, pharmaceutical compositions comprising thereof and the use of dasatinib salts the treatment of cancer.

The invention claimed is: 
     
       1. A Dasatinib product, which is
 Dasatinib cyclamic acid salt, which is in amorphous or crystalline form, and/or is a hydrate or solvate thereof; 
 Dasatinib hydrogen bromide (1:2) salt having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 19.75; 24.39; 29.82; 
 Dasatinib methane sulfonic acid (1:2) salt having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 4.26; 17.52; 22.66; 
 Dasatinib p-toluenesulfonic acid (1:1) dihydrate salt having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 6.41; 17.68; 19.41; 
 anhydrous Dasatinib p-toluenesulfonic acid (1:1) salt Form I having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 10.21; 12.77; 16.74; 
 anhydrous Dasatinib p-toluenesulfonic acid (1:1) salt Form II having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 12.17; 14.57; 24.42; or 
 Dasatinib p-toluenesulfonic acid (1:1) salt methanol solvate having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 18.36; 19.50; 22.52. 
 
     
     
       2. The Dasatinib product according to  claim 1 , which is Dasatinib cyclamic acid (1:1) salt Form I having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 10.11; 18.81; 19.83. 
     
     
       3. The Dasatinib product according to  claim 1 , which is Dasatinib cyclamic acid (1:1) salt Form II having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 4.24; 8.43; 14.80. 
     
     
       4. The Dasatinib product according to  claim 1 , which is Dasatinib hydrogen bromide (1:2) salt having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 19.75; 24.39; 29.82. 
     
     
       5. The Dasatinib product according to  claim 1 , which is Dasatinib methane sulfonic acid (1:2) salt having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 4.26; 17.52; 22.66. 
     
     
       6. The Dasatinib product according to  claim 1 , which is Dasatinib p-toluenesulfonic acid (1:1) dihydrate salt having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 6.41; 17.68; 19.41. 
     
     
       7. The Dasatinib product according to  claim 1 , which is anhydrous Dasatinib p-toluenesulfonic acid (1:1) salt Form I having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 10.21; 12.77; 16.74. 
     
     
       8. The Dasatinib product according to  claim 1 , which is anhydrous Dasatinib p-toluenesulfonic acid (1:1) salt Form II having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 12.17; 14.57; 24.42. 
     
     
       9. The Dasatinib product according to  claim 1 , which is Dasatinib p-toluenesulfonic acid (1:1) salt methanol solvate having the following characteristic X-ray powder diffraction peaks: 2θ (±0.2 °2θ): 18.36; 19.50; 22.52. 
     
     
       10. A process for preparing the Dasatinib product according to  claim 1 , comprising reacting Dasatinib base in an organic solvent or in a mixture of an organic solvent and water with an organic or inorganic acid and separating the Dasatinib salt formed. 
     
     
       11. The process according to  claim 10 , wherein the organic or inorganic acid is hydrogen-bromide, cyclamic acid, methansulfonic acid, or p-toluenesulfonic acid, and after separating the Dasatinib salt formed, optionally drying. 
     
     
       12. The process according to  claim 11 , wherein 0.3-3.0 molar equivalent amount of acid is reacted. 
     
     
       13. The process according to  claim 11 , wherein the organic solvent is selected from the group consisting of C 1-4  aliphatic alcohols, linear symmetric ketones, or asymmetric ketones, C 1-5  linear ethers, ring ethers, C 1-6  esters, and dipolar-aprotic solvents, or is a mixture thereof or an aqueous mixture thereof. 
     
     
       14. The process according to  claim 13  wherein the organic solvent is tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, acetone, methanol, ethanol, 2-propanol, or methyl-ethyl-ketone or a mixture thereof or an aqueous mixture thereof. 
     
     
       15. The process according to  claim 10 , wherein the reaction is carried out at a temperature between 0° C. and the boiling point of the solvent. 
     
     
       16. A pharmaceutical composition, comprising the Dasatinib product according to  claim 1  in an admixture with one or more pharmaceutical auxiliary agents. 
     
     
       17. A method for preparing the pharmaceutical composition according to  claim 16 , comprising admixing a therapeutically effective amount of said Dasatinib product with a pharmaceutically acceptable carrier and optionally with further pharmaceutically acceptable auxiliary agents and bringing the mixture into a galenic form. 
     
     
       18. A method of treating cancer, including chronic myeloid leukemia in a patient comprising administering to said patient an effective amount of the Dasatinib product according to  claim 1 . 
     
     
       19. The Dasatinib product according to  claim 1 , which has the following characteristic X-ray powder diffraction pattern as depicted in:
   FIG. 1  for the Dasatinib cyclamate (1:1) Form I; 
   FIG. 2  for the Dasatinib cyclamate (1:1) Form II; 
   FIG. 3  for the Dasatinib hydrogen bromide (1:2) salt; 
   FIG. 4  for the Dasatinib mesilate (1:2); 
   FIG. 5  for the Dasatinib tosilate (1:1) dihydrate; 
   FIG. 6  for the anhydrous Dasatinib tosilate (1:1) Form I; 
   FIG. 7  for the anhydrous Dasatinib tosilate (1:1) Form II; or 
   FIG. 8  for the Dasatinib tosilate (1:1) methanol solvate. 
 
     
     
       20. The Dasatinib product according to  claim 1 , which has the following characteristic X-ray powder diffraction peaks (±0.2 °2θ):
 for the Dasatinib cyclamic acid (1:1) salt Form I: 7.64; 10.11; 13.74; 18.81; 19.83; 21.49; 21.78; 22.94; 24.79; 31.59; 
 for the Dasatinib cyclamate (1:1) Form II: 4.24; 8.43; 8.73; 12.34; 14.80; 17.25; 20.81; 21.12; 25.91; 26.54; 
 for the Dasatinib hydrogen bromide (1:2) salt: 10.98; 11.51; 12.32; 16.07; 19.75; 21.67; 24.39; 24.78; 29.82; 32.20; 
 for the Dasatinib mesilate (1:2): 4.26; 9.86; 10.16; 13.66; 17.52; 18.13; 20.33; 22.66; 28.45; 30.97; 
 for the Dasatinib tosilate (1:1) dihydrate: 6.41; 11.79; 13.05; 13.80; 17.68; 18.55; 19.41; 20.73; 22.51; 23.96; 
 for the anhydrous Dasatinib tosilate (1:1) Form I: 10.21; 11.09; 12.77; 13.75; 16.74; 17.76; 18.68; 19.95; 21.32; 29.04; 
 for the anhydrous Dasatinib tosilate (1:1) Form II: 6.37; 9.54; 11.90; 12.17; 14.22; 14.57; 18.39; 19.78; 24.42; 25.46; or 
 for the Dasatinib tosilate (1:1) methanol solvate: 6.35; 9.25; 13.83; 18.36; 19.50; 21.48; 22.52; 24.02; 24.94; 27.16. 
 
     
     
       21. The Dasatinib product according to  claim 1 , which is Dasatinib cyclamic acid salt in crystalline form.